Evidence map›Paper›PMID 32906212›Full record

ArticleHuman mutation2020

Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment.

Roxanne L Simmons, Haiyan Li, Baris Alten, Magda S Santos, Ruiji Jiang, Brianna Paul, Sanam J Lalani, Audrey Cortesi, Kendall Parks, Nitin Khandelwal and 10 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human mutation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
1.2field-weighted citation impact, top 24% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

16 citing papers in PubMed, 18 citations in OpenAlex.

  1. Article
  2. Review
  3. Synaptobrevin-2 disease variants reveal spatial constraints within the presynaptic active zone.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Molecular syndromology · 2023
    Article
  9. Article
  10. Genetic disorders of neurotransmitter release machinery.Frontiers in synaptic neuroscience · 2023
    Review
  11. Review
  12. Article
  13. Article
  14. A NovelInternational journal of molecular sciences · 2021
    Article
  15. Article
  16. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 8 institutions in 1 country.

Roxanne L SimmonsDepartment of Neurology, Weill Institute for Neurosciences and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Haiyan LiDepartment of Psychiatry, Weill Institute for Neurosciences and Kavli Institute for Fundamental Neuroscience, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Baris AltenDepartment of Pharmacology and Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee, USA.
Magda S SantosDepartment of Psychiatry, Weill Institute for Neurosciences and Kavli Institute for Fundamental Neuroscience, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Ruiji JiangDepartment of Neurology, Weill Institute for Neurosciences and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Brianna PaulDepartment of Neurology, Weill Institute for Neurosciences and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Sanam J LalaniDepartment of Neurology, Weill Institute for Neurosciences and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Audrey CortesiDepartment of Neurology, Weill Institute for Neurosciences and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Kendall ParksDepartment of Neurology, Weill Institute for Neurosciences and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Nitin KhandelwalDepartment of Neuroscience, UT Southwestern Medical Center, Dallas, Texas, USA.
Bethany Smith-PackardDepartment of Pediatrics, Penn State Health Pediatric Specialties, Hershey, Pennsylvania, USA.
Malay A PhoongDivision of Neuroscience, Department of Pediatric Neuropsychology, Sutter Medical Foundation, Sacramento, California, USA.
Michael ChezNeuroscience Medical Group, Sutter Medical Foundation, Sacramento, California, USA.
Heather FisherDepartment of Genetics, Children's Medical Center of Texas, Dallas, Texas, USA.
Angela E ScheuerleDivision of Genetics and Metabolism, Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA.
Marwan ShinawiDivision of Genetics and Genomic Medicine, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA.ORCID 0000-0003-1329-4100
Shaun A HussainDepartment of Pediatrics, UCLA Mattel Children's Hospital and Geffen School of Medicine, Los Angeles, California, USA.
Ege T KavalaliDepartment of Pharmacology and Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee, USA.
Elliott H SherrDepartment of Neurology, Weill Institute for Neurosciences and Institute of Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.
Susan M VoglmaierDepartment of Psychiatry, Weill Institute for Neurosciences and Kavli Institute for Fundamental Neuroscience, School of Medicine, University of California, San Francisco, San Francisco, California, USA.ORCID 0000-0002-1211-8108
University of California, San Francisco · USSouthwestern Medical Center · USSutter Medical Center · USVanderbilt University · USChildren's Medical Center · USMattel Children's Hospital · USPenn State Milton S. Hershey Medical Center · USSt. Louis Children's Hospital · US

Funding

De novo copy number variation and gene discovery in human brain malformationsR01NS058721 · NINDS · UNIVERSITY OF CHICAGO · PI ARGILLI, EMANUELA · 2008 to 2025
$10.9M
Role of SNARE Interactions in Central Synapse FunctionR01MH066198 · NIMH · VANDERBILT UNIVERSITY · PI KAVALALI, EGE T · 2004 to 2023
$7.9M
Membrane Trafficking of Vesicular Neurotransmitter TransportersR01MH083691 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI VOGLMAIER, SUSAN M. · 2011 to 2022
$3.9M
Investigating sex differences in DDX3X mouse modelsR01NS120667 · NINDS · DUKE UNIVERSITY · PI SILVER, DEBRA L. · 2021 to 2025
$3.4M
NIMH NIH HHS MH066198NIMH NIH HHS MH083691NIMH NIH HHS R01 MH066198NIMH NIH HHS R01 MH083691NINDS NIH HHS R01 NS058721NINDS NIH HHS R01 NS120667
6 · The paper itself

Abstract

Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle-associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop-gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live-cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild-type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off-label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment.

Indexed as

4-AminopyridineAdultElectrophysiologyExocytosisFemaleHumansMaleMutationSynaptic TransmissionSynaptic VesiclesVesicle-Associated Membrane Protein 24-AminopyridineVesicle-Associated Membrane Protein 2aminopyridineneurodevelopmental disordersynaptic transmissionsynaptic vesicleVAMP2

Identifiers

PMID32906212
PMCPMC10898792
OpenAlexW3085455577

What OpenQuestion holds

Textmetadata
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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.